Novel antihypertensive benzopyran derivatives

ABSTRACT

Disclosed herein are novel benzopyrans having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of hypertension.

This is a continuation-in-part of copending U.S. Ser. No. 146,875, filedJan. 22, 1988, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel benzopyrans havingpharmacological activity, to a process for preparing them, topharmaceutical compositions containing them, and to their use in thetreatment of hypertension.

European Patent Publication 158,923 discloses classes of chromans thatare described as having blood pressure lowering activity.

The present invention discloses compounds represented by formula (I)##STR1## wherein R¹ is trifluoromethoxy or β,β,β-trifluoroethoxy; R² andR³ are independently selected from the group consisting of hydrogen,lower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing5 to 8 carbon atoms, ##STR2## or R² and R³ are joined to form CH_(2n)wherein n is 4 to 7; or R² and R³ are joined together to form ##STR3##wherein m is 3 to 6; or R² and R³ are joined together to form ##STR4##

wherein R⁴ is selected from the group consisting of hydrogen, alkoxycontaining 1 to 5 carbon atoms, amino or mono- or disubstituted alkylamino wherein said alkyl groups contain 1 to 5 carbon atoms and thepharmaceutically acceptable salts and solvates thereof.

A preferred aspect of the present invention are compounds of formula (I)wherein R¹ is trifluoromethoxy and R² and R³ are joined to form ##STR5##

The compounds of formula (I), are asymmetric and, therefore, can existin the form of optical isomers. The present invention extends to allsuch isomers individually and as mixtures, such as racemicmodifications.

Preferably, a compound of formula (I) is in substantially pure form.

Examples of compounds of formula (I) include the compounds prepared inthe Examples hereinafter.

The present invention also provides a process for the preparation of acompound of formula (I), which comprises the reaction of a compound offormula (II) ##STR6## wherein R₁ ¹ is R¹ as defined hereinbefore or agroup or atom convertible thereto, with a compound of formula (III)##STR7## wherein X is chlorine, bromine, or iodine; R⁴ is as definedabove; and p is 1 or 2.

It is particularly preferred that the reaction between the compounds offormula (II) and (III) is carried out under alkylation conditions so asto facilitate the formation of the desired bonds, for example, byheating in the presence of potassium carbonate.

Examples of conversions of a group or atom from R₁ ¹ into R¹ aregenerally known in the art of synthetic chemistry. For example, if it isdesired to obtain a compound of formula (I) wherein R¹ is atrifluoroethoxy group it is possible to convert a compound of formula(I) wherein R₁ ¹ is a hydroxy group or a protected hydroxy group to thedesired trifluoroethoxy group by deprotecting the hydroxy group andalkylating the hydroxy group in a conventional manner. Examples ofprotecting agents and their addition and removal are generally known inthe art.

The compounds of this invention are capable of forming acid additionsalts with therapeutically acceptable acids. The acid addition salts areprepared by reacting the base form of the appropriate compound offormula (I) with one or more equivalents, preferably with an excess, ofthe appropriate acid in an organic solvent, for example, diethyl etheror an ethanol diethyl ether mixture.

These salts, when administered to a mammal, possess the same or improvedpharmacologic activities as the corresponding bases. For many purposesit is preferable to administer the salts rather than the basiccompounds. Suitable acids to form these salts include the common mineralacids, e.g. hydrohalic, sulfuric or phosphoric acid; the organic acids,e.g. ascorbic, citric, lactic, aspartic or tartaric acid; and acidswhich are sparingly soluble in body fluids and which impart slow-releaseproperties to their respective salts, e.g. pamoic or tannic acid orcarboxymethyl cellulose. The preferred salt is the hydrochloride salt.The addition salts thus obtained are the functional equivalent of theparent base compound in respect to their therapeutic use. Hence, theseaddition salts are included within the scope of this invention and arelimited only by the requirement that the acids employed in forming thesalts be therapeutically acceptable.

The compounds of formula (II) are novel compounds and can be prepared inaccordance with the processes described herein.

The compounds of formula (III) are known compounds or can be prepared byconventional procedures from known compounds.

As mentioned previously, the compounds of formula (I) have been found tohave blood-pressure lowering activity. They are therefore useful in thetreatment of hypertension.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention and a pharmaceuticallyacceptable carrier. In particular, the present invention provides ananti-hypertensive pharmaceutical composition which comprises anantihypertensive effective amount of a compound of this invention and apharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as a filler, a disintegrating agent, a binder, alubricant, a flavouring agent and the like. They are formulated inconventional manner, for example in a manner similar to that used forknown antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula (I) are ofparticular use in the treatment of hypertension.

The present invention further provides a method of treating hypertensionin mammals including man, which comprises administering to the afflictedmammal an antihypertensive effective amount of a compound or apharmaceutical composition of the invention.

Synthetic Process A relates to the preparation of a compound of formula(I) ##STR8## wherein R¹ is as defined above; X is chlorine, bromine oriodine; R⁶ is benzoyl, furoyl, or ##STR9## wherein p is 1 or 2; R⁷ islower alkyl containing 1 to 5 carbon atoms, cyclo lower alkyl containing5 to 8 carbon atoms, or benzyl; R⁸ is benzoyl or furoyl; and R⁴ is asdefined above.

The production of preferred compounds of the present invention isillustrated by Synthetic Process B. ##STR10##

The resolution of compounds of formula (I) into optical isomers may beaccomplished by reacting the racemate with an optically pure chiralauxiliary, preferably 1-(1-naphthyl)ethyl isocyanate or α-methylbenzylisocyanate, to form a mixture of two diastereomers. These diastereomersare then separated by physical means, such as chromatography orcrystallization. Each is reacted to remove the chiral auxiliary toafford the enantiomers of compounds of formula (I).

Synthetic Process C relates to the resolution of a preferred compound offormula (I). ##STR11##

The following Examples further illustrate this invention.

EXAMPLE 1 Preparation of p-Trifluoromethoxy Phenol

p-Trifluoromethoxy aniline (49.60 g) was added rapidly dropwise tovigorously stirred 9N aqueous H₂ SO₄ (500 mL) at 40° C. The mixture washeated to dissolve the solid, then cooled to 0° C. To the fine whitesuspension, a solution of sodium nitrite (19.46 g in 50 mL of H₂ O) wasadded portionwise until an immediate positive KI/starch test result wasobtained. This cold solution of diazonium salt was added rapidlydropwise to 9N aqueous H₂ SO₄ (500 mL) at 110° C. Stirring and heatingwas continued for 2.5 hours. The mixture was cooled to 10° C. andextracted with diethyl ether (3×500 mL). The combined organic layerswere dried (MgSO₄), filtered and evaporated in vacuo, then flashchromatographed on SiO₂ using diethyl ether as eluant to give 35.0 g ofthe desired phenol as a light brown oil. The oil was distilled(b.p.=75°-80° C. at 20 torr.) to afford a yellow liquid.

NMR (CDCl₃): δ 5.06(1H, s), 6.83(2H, d, J=9.2), 7.11(2H, d, J=9.2 Hz)

EXAMPLE 2 Preparation of1-[(1,1-Dimethyl-2-propynyl)oxy]-4-(trifluoromethoxy)benzene

To a solution of p-trifluoromethoxy phenol (30.69 g), and2-methyl-2-chloro-3-butyne (53.00 g) in dry acetonitrile (350 mL) wasadded potassium iodide (14.30 g) followed by potassium carbonate (92.25g). This reaction mixture was heated at 70°-80° C. for four days thencooled to room temperature and filtered through celite. The precipitatewas washed with dichloromethane and the washings were added to theacetonitrile. The organics were evaporated in vacuo and the oil wastaken up in 250 mL of dichloromethane. The organics were washed withwater (2×100 mL) and dilute aqueous sodium thiosulfate (2×100 mL), dried(MgSO₄), filtered and evaporated in vacuo to leave a dark brown-orangeoil. Flash column chromatography on SiO₂ using hexane/Et₂ O (5/1)afforded 34.73 g of the pure product.

NMR (CDCl₃) δ 1.64(6H, s), 2.60(1H, s), 7.05-7.30(4H, m)

EXAMPLE 3 Preparation of 2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran

A solution of 1-[(1,1-dimethyl-2-propynyl)oxy]-4-trifluoromethoxybenzene(16.25 g) in 60 mL of quinoline was heated to 175° C. for 2 hours. Thesolution was cooled to room temperature then ether (250 mL) was added.This mixture was stirred for 15 minutes then decanted from anyprecipitated tars. The ether solution was washed with 1N aqueoushydrochloric acid (3×200 mL) then water (1×200 mL) and dried (K₂ CO₃).The filtered ether solution was evaporated and flash chromatographed onSiO₂ using hexane/ethyl acetate (5/1) as eluant to afford 13.92 g (85%)of the desired bicyclic compound.

Alternate Preparation of2,2-Dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran

A solution of the1-[(1,1-dimethyl-2-propynyl)oxy]-4-trifluoromethoxybenzene (29.05 g) in100 mL of chlorobenzene (b.p.=132° C.) was heated to reflux for 24hours. The reaction mixture was cooled and the solvent removed in vacuo.The oily residue was flash chromatographed on SiO₂ using hexane/ethylacetate (5/1) as eluant to afford 19.72 g of the desired bicycliccompound.

NMR (CDCl₃) δ 1.42 (6H, s), 5.67 (1H, d, J=10 Hz), 6.28 (1H, d, J=10Hz), 6.78 (1H, d, J=5.5 Hz), 6.83 (1H, d, J=2H), 6.94 (1H, dd, J=5.5 Hz,2 Hz)

EXAMPLE 4 Preparation of1a,7b-Dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-oxireno[c][1]benzopyran

To a solution of 2,2-dimethyl-6-trifluoromethoxy-2H-1-benzopyran (14.37g) in dichloromethane (40 mL) at 0° C. was added a solution ofm-chloroperoxybenzoic acid (mCPBA) (14.22 g) in dichloromethane (160 mL)dropwise. After the addition was complete the ice bath was removed andthe temperature allowed to warm slowly to 15° C. whilst stirring for 18hours. The reaction mixture was filtered, and the precipitate was washedwith dichloromethane (50 mL). The combined filtrate was washed with 25%aqueous sodium thiosulfate (2×100 mL), and 50% aqueous sodiumbicarbonate (2×100 mL), dried (MgSO₄), filtered and evaporated in vacuo.The orange oil was flash chromatographed on SiO₂ using hexane/ether(4/1) as eluant to afford 13.36 g of the epoxide as a light yellow oil,which solidified upon standing.

NMR (CDCl₃) δ 1.25 (3H, s), 1.58 (3H, s), 3.49 (1H, d, J=4 Hz), 3.86(1H, d, J=4 Hz), 6.78 (1H, d, J=8.5 Hz), 7.11 (1H, dd, J=8.5 Hz and 2Hz), 7.22 (1H, d, J=2 Hz)

EXAMPLE 5 Preparation oftrans-2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine

To a solution of1a,7b-dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-oxireno[c][1]benzopyran(6.18 g) in absolute ethanol (30 mL) at 0° C. was added ammoniumhydroxide (45 mL). The reaction mixture was capped with a rubber septumand stirred for four days. The reaction mixture was evaporated in vacuoto remove ethanol and water and the oil was taken up in dichloromethane,dried (Na₂ SO₄) filtered and concentrated in vacuo. The residue wasflash chromatographed on SiO₂ using dichloromethane/methanol (5/1) aseluant to afford the amino-alcohol, m.p. 176°-182° C. (dec.)recrystallized from chloroform.

Two of the above reactions were run simultaneously to obtain 8.95 g ofproduct.

NMR (DMSO-d₆) δ 1.07 (3H, s), 1.35 (3H, s), 3.20 (1H, d, J=9.2 Hz), 3.52(1H, d, J=9.2 Hz), 6.76 (1H, d, J=9 Hz), 7.08 (1H, dd, J=9 Hz, 1.5 Hz),7.51 (1H, d, J=1.5 Hz)

EXAMPLE 6 Preparation oftrans-2-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one

To a solution oftrans-2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine(13.86 g) and methyl 2-formylbenzoate (9.03 g) in 200 mL of dry methanolwas added 120 mL of a 0.5 molar solution of zinc chloride-sodiumcyanoborohydride (0.06 moles eash) in dry methanol. After one hour themixture was warmed to 50°-55° C. and held there with stirring for 14hours.

The cooled reaction mixture was quenched with 120 mL of saturatedaqueous sodium bicarbonate and the methanol was removed in vacuo. 120 mLof water was added to the residue which was then extracted withdichloromethane (3×200 mL). The combined extracts were washed with water(2×300 mL), dried over K₂ CO₃, filtered then evaporated to leave anoff-white solid.

This solid was dissolved in 500 mL of hot toluene; the mixture was thenheated to reflux for 4 to 5 hours. The solution was then cooled and awhite precipitate began to form. The mixture was cooled to 0° C. for 0.5hours during which time a thick mass of white crystals formed. Thesecrystals were collected by vacuum filtration, washed with hexane/toluene(4/1) and dried in vacuo to yield 18.30 g (93%) of analytically pureproduct as a white flocculent solid, m.p. 212°-213° C.

Alternate Preparation oftrans-2-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one

To a solution oftrans-2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-4-amine(3.85 g) and methyl 2-bromomethylbenzoate (3.11 g) in dry acetonitrile(80 mL) was added potassium iodide (1.13 g) then potassium carbonate(powdered, 5.63 g). The reaction mixture was stirred under nitrogen atroom temperature for 1 hour then heated in a 75°-80° C. oil bath for 24hours. The cooled mixture was vacuum filtered through celite. Theprecipitate was washed with ethyl acetate (75 mL), and the filtrateswere combined and evaporated. The residue was taken up in ethyl acetate(175 mL), washed with water (2×100 mL) then 25% aqueous sodiumthiosulfate (2×100 mL), dried (MgSO₄), filtered and evaporated in vacuo.The resultant oil was crystallized from dichloromethane/ethyl acetate(5/1). The crystals were collected, washed with ether, and dried invacuo to afford the desired compound in 48% yield, m.p. 212°-213° C.

NMR (DMSO-d₆) δ 1.24 (3H, s), 1.46 (3H, s), 3.91 (1H, br), 4.06 (1H, brd), 4.48 (1H, br d), 5.24 (1H, br s), 5.77 (1H, d, J=5.8 Hz), 6.70 (1H,br s), 6.92 (1H, d, J=8.9 Hz), 7.17 (1H, dd, J=8.9 Hz and 2.6 Hz),7.50-7.66 (3H, m), 7.78 (1H, d, J=7.5 Hz)

Anal. Calcd.: C, 61.07; H, 4.61; N, 3.56; Found: C, 60.92; H, 4.87; N,3.35.

EXAMPLE 7 Preparation oftrans-N-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2-furancarboxamide

To a solution of trans-2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-2H-1-benzopyran-1-benzopyran-4-amine(3.40 g) and triethylamine (1.84 mL) in dichloromethane (60 mL) at 5° C.was added 2-furoyl chloride (1.30 mL) dropwise via a pipet. After 10minutes the ice water bath was removed and the reaction was stirred andallowed to raise to ambient temperature. TLC at 2.5 hours indicatedcomplete reaction and the mixture was increased in volume by adding 60mL of dichloromethane. The organics were washed with 0.1N aqueous HCl(2×80 mL), 50% aqueous sodium bicarbonate (2×80 mL) and water (1×80 mL),dried (MgSO₄), filtered and evaporated in vacuo. The oily residue wasflash chromatographed on SiO₂ using dichloromethane/ethyl acetate (8/1)as eluant to leave a colorless oil. The desired compound wascrystallized from ether/hexane (1/1) to give white needles, m.p.146°-147° C. yield 50%.

NMR (DMSO-d₆) δ 1.16 (3H, s), 1.39 (3H, s), 3.74 (1H, dd, J=5.9 Hz and9.8 Hz), 4.96 (1H, t, J=9.3 Hz), 5.65 (1H, d, J=6 Hz), 6.64 (1H, m),6.86 (1H, d, J=9 Hz), 6.93 (1H, d, J=2.6 Hz), 7.14 (1H, dd, J=9 Hz and2.6 Hz), 7.17 (1H, d, J=2.6 Hz), 7.86 (1H, s), 8.73 (1H, d, J=9 Hz).

Anal. Calcd.: C, 54.99; H, 4.34; N, 3.77; Found: C, 54.79; H, 4.67; N,3.71.

The following Examples illustrate the resolution of the compounds ofthis invention into optical isomers.

EXAMPLE 8 Preparation of (+)- and(-)-(trans)-[1-(1-naphthalenyl)ethyl]carbamic

Acid4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-3,4-dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-3-ylEster

A solution oftrans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one(8.53 g) and S-(+)-1-(1-naphthyl)ethyl isocyanate (5.15 g) in drytoluene (275 mL) was heated at 110°-115° C. for 24 hours. The cooledmixture was evaporated in vacuo, then flash chromatographed on silicagel (1 kg) using dichloromethane/hexane/ethyl acetate (6/6/1) as eluantto afford the following: (a) 4.74 g of diastereomer A, (b) 3.75 g of amixture of both diastereomers and (c) 4.20 g of diastereomer B.

Pure diastereomer (A): glass, [α]_(D) ²⁵ =+2.0, c=1, CHCl₃

NMR (CDCl₃): δ 1.25 (3H, d), 1.33 (3H, s), 1.42 (3H, s), 4.09 (1H, AB d,J=16.4 Hz), 4.59 (1H, AB, d, J=16.4 Hz), 5.12 (NH, d, J=8.2 Hz), 5.20(1H, d, J=10.5 Hz), 5.33 (1H, m), 5.76 (1H, d, J=10.5 Hz), 6.78 (1H, d,J=3.0 Hz), 6.88 (1H, d, J=8.9 Hz), 7.07 (1H, dd, J=8.9 Hz and 3.0 Hz),7.38-7.60 (7H, m) and 7.70-8.00 (4H, m)

Pure diastereomer (B): glass, [α]_(D) ²⁵ =-38.0°, c=1, CHCl₃

NMR (CDCl₃): δ 1.40 (3H, s), 1.51 (3H, s), 1.53 (3H, d, J=7.0 Hz), 3.96(1H, AB d, J=16.3 Hz), 4.40 (1H, AB d, J=16.3 Hz), 5.23 (1H, d, J=10.6Hz), 5.25 (NH, d), 5.39 (1H, m), 5.76 (1H, d, J=10.6 Hz) and 6.68-7.87(14H, series of m)

In addition, this experiment was repeated using S--(--)-- α-methylbenzylisocyanate as the chiral auxiliary. The purified and separateddiastereomers were crystallized by diffusion of hexane into an ethylacetate solution.

EXAMPLE 9 Preparation of(-)-3S,4R-trans-2-[2,3-Dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one

To a solution of (-)-(trans)-[1-(1-naphthalenyl)ethyl]carbamic acid4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3,4-dihydro-2,2-dimethyl-6-(trifluoromethoxy)-2H-1-benzopyran-3-ylester, diastereomer B, (5.86 g) in dichloromethane (150 mL) at roomtemperature was added triethylamine (3.49 mL) followed by the dropwiseaddition of trichlorosilane (2.53 mL). This mixture was stirred at roomtemperature for 6 hours then warmed to 40° C. for 18 hours. The cooledmixture was quenched with 140 mL of 2M aqueous ammonium hydroxide. Thismixture was stirred for 30 minutes. Celite was added to the mixture andthen it was filtered. The precipitate was placed into a flask and washedwith good agitation with dichloromethane (100 mL). This mixture wasfiltered and the filtrates were combined in a separatory funnel. Theorganic layer was washed with water, dried (K₂ CO₃) and evaporated invacuo. The residue was flash chromatographed on silica gel using ethylether/hexane (4/1) as eluant. The desired product was crystallized fromhot hexane/ethyl ether (2/1), m.p. 172°-172.5° C.

[α]_(D) ²⁵ =-59.50°, c=1, CHCl₃

The NMR of this product is substantively the same as for the product ofExample 6.

Pharmacological Data

Male Okamoto-Aoki spontaneously hypertensive rats (SHR) ranging inweight from 250-400 g were anesthetized with halothane. Their leftfemoral arteries and veins were cannulated with polyethylene tubing ofthe appropriate size (i.d. 0.023", o.d. 0.038"). Each animal was placedin a Bollman cage, and the tail, along with two cannulas, was extendedthrough a hole in one end of the cage. The tail was taped securely to afirm rubber board to prevent the rat from turning in its cage todislodge the cannulas. The femoral arterial cannula was connected to aStatham pressure transducer which in turn was attached to a polygraphfor recording arterial pressure and pulse rate. The pulse rate wasconsidered to be the heart rate.

After the blood pressure has stabilized (usually 2 hours after cessationof the anesthesia), standard agonists were injected by the i.v. route.The doses administered were: isoproterenol 0.5 μg/kg, adrenaline 2.0μg/kg, tyramine 200 μg/kg and angiotensin-I 0.25 μg/kg. The agonistswere given in random order except that tyramine was never preceded byisoproterenol as the response to tyramine seemed to be blunted after aprior injection of isoproterenol. Enough time was allowed for the BP toreturn to preinjection levels before the test compound was administeredby gastric lavage. The time of drug administration was designated astime zero. Heart rate and blood pressure were recorded at 5, 10, 15, 30,45 and 60 minutes and hourly thereafter for a period of 4 hours afterdrug administration. At 1 and 2 hours post-drug the agonists were againinjected at the same concentration and in the same order as during thecontrol period.

For each compound the maximum mean fall in blood pressure was comparedto pretreatment control values and expressed as a percentage fall inblood pressure.

    __________________________________________________________________________    Blood Pressure Lowering by Compound of Formula (I)                             ##STR12##                                         (I)                        __________________________________________________________________________                                         Heart Rate                                                    Blood Pressure  Pre-                                                          Pre-            treat.                                                        treat.          HR                                                     mg/kg  MABP                                                                              Max Δ BP                                                                            beats/                                                                            Max Δ HR                       R.sup.1                                                                             R.sup.2 and R.sup.3                                                                   p.o.                                                                              n  mm Hg                                                                             mm Hg   %   min.                                                                              beats   %                            __________________________________________________________________________    CF.sub.3 O                                                                           ##STR13##                                                                            10 0.5                                                                             3 178 181                                                                           -93 at 4 Hr -56 at 4 Hr                                                               -52 -31                                                                           351 364                                                                           +87 at 4 Hr +89 at 4                                                                  +25 +24                            3S, 4R  0.05                                                                               6 183 -13 at 3 Hr                                                                           -7  415 -11 at 3 Hr                                                                           -3                                 enantiomer                                                                            0.13                                                                               8 178 -35 at 2 Hr                                                                           -20 369 +34 at 2 Hr                                                                           +9                                         0.25                                                                              10 172 -49 at 1 Hr                                                                           -29 378 +65 at 1 Hr                                                                           +17                                                   -48 at 5 Hr                                                                           -28                                                        0.5  8 180 -75 at 45 min                                                                         -42 402 +75 at 45 min                                                                         +19                                                   -75 at 5 Hr                                                                           -42     +49 at 5 Hr                                                                           +12                          __________________________________________________________________________                                          Heart Rate                                                     Blood Pressure Pre-                                                           Pre-           treat.                                                         treat.         HR                                                       mg/kg MABP                                                                              Max Δ BP                                                                           beats/                                                                            Max Δ HR                      R.sub.1                                                                            R.sub.2  R.sub.3                                                                          p.o.                                                                              n mm Hg                                                                             mm Hg   %  min.                                                                              beats   %                           __________________________________________________________________________    CF.sub.3 O                                                                          ##STR14##                                                                             H  10  4 176 -96 at 30 min                                                                         -55                                                                              423 +57 at 30 min                                                                         +13                              Control      0  6 172 -5 at 3 Hr                                                                            -3 372 +21 at 4 Hr                                                                           +6                          __________________________________________________________________________

Compounds of formula (I) may be administered alone or with a diuretic,such as hydrochlorothianzide, or a β-blocker, such as propranolol orcetamolol in a suitable unit dose form.

We claim:
 1. A compound of formula (I) ##STR15## wherein R¹ istrifluoromethoxy or β,β,β-trifluoroethoxy; R² and R³ are independentlyselected from the group consisting of hydrogen, lower alkyl containing 1to 5 carbon atoms, cyclo lower alkyl containing 5 to 8 carbon atoms,##STR16## or R² and R³ are joined to form CH_(2n) wherein n is 4 to 7;or R² and R³ are joined together to form ##STR17## wherein m is 3 to 6;or R² and R³ are joined together to form ##STR18## wherein R⁴ isselected from the group consisting of hydrogen, alkoxy containing 1 to 5carbon atoms, amino or mono- or disubstituted alkyl amino wherein saidalkyl groups contain 1 to 5 carbon atoms and the pharmaceuticallyacceptable salts and solvates thereof.
 2. The compound according toclaim 1 designatedtrans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-oneand the pharmaceutically acceptable salts thereof.
 3. The compoundaccording to claim 1 designatedtrans-N-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2-furancarboxamideand the pharmaceutically acceptable salts thereof.
 4. The compoundaccording to claim 2 designated(-)-3S,4R-trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-(trifluoromethoxy)-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-oneand the pharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier for use in the treatment ofhypertension.
 6. A method of treatment of hypertension in mammals whichcomprises administering to the mammal in need thereof an effectiveantihypertensive amount of a compound of formula (I) according to claim1.